Estrogens are thought of as female hormones because they are secreted from the ovaries, but they are also synthesized in other tissues, including tissues in men. Estrogens have many different actions in the body, most are well known and are associated with reproduction, the stimulation of tissues such as: uterus, vagina, breast, pituitary and brain; but they also have well-known actions on non-reproductive tissues, such as liver and bone. More recently these sex steroids have been shown to be involved in other previously unsuspected actions in the brain, such as learning, memory and cellular protection, involving them in pathological states such Alzheimer's disease, stroke, depression, and schizophrenia. The action of estrogens in all cells is mediated by the estrogen receptor (ER); of which there are two major forms, ER1 and ER2. They are both present in the brain, and alterations in their concentration through estrogen deprivation or other factors are thought to lead to the above pathologies. It is our intention to develop two estrogens labeled with the radioactive tracer 123I for use in SPECT imaging ERs in the brain. We will develop methods for rapid and high yield synthesis of two 123I-estrogens, 112-methoxy-[161-123I]iodoestradiol (which binds specifically to ER1) and 112-methoxy-(E-171-2'-[123I]iodovinyl)-estradiol (which binds equally to both ER1 and ER2). These radioactive estrogens will be injected into living baboons and the regions of the brain that concentrate the tracers by ER- mediated binding will be imaged. Control experiments in which the concentration of the tracers is blocked with compounds that bind specifically ER1 and ER2 will confirm the specificity of binding. These experiments will provide a unique mechanism to study this important receptor system in humans suffering from major neuropsychiatric disorders and allow the development of better treatments. PUBLIC HEALTH RELEVANCE It is thought that changes in brain content of the proteins that produce estrogenic responses, estrogen receptors, are involved in several neurological disorders, including Alzheimer's and Parkinson's diseases, multiple sclerosis and epilepsy, as well other disorders of learning and memory. The aim of this application is to synthesize two different radioactive estrogens labeled with 123I and demonstrate that they can be used in live baboons to image the two major estrogen receptors, ER1 and ER2, in the brain. These studies will demonstrate the potential of monitoring this important system in neurodegenerative diseases of humans. [unreadable] [unreadable] [unreadable]